CORE: Neuropathology & Genetics Core C Core Leader: John Q. Trojanowski; Co-Core Leaders: Edward B. Lee and Vivianna Van Deerlin Core Summary/Abstract The Neuropathology and Genetics Core C in the renewal of this NINDS Morris K. Udall Parkinson's Disease Research Center of Excellence (Center) at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) banks and characterizes postmortem brain tissue collected from clinically assessed Parkinson's disease (PD) patients without and with cognitive impairments (CI) or dementia (PDD) and dementia with Lewy body (DLB) patients followed in Core B as well as multiple system atrophy (MSA) patients in addition to age matched controls. It also collects DNA from these subjects. PD, PDD and DLB (referred to as Lewy body disorders or LBD) as well as MSA are a spectrum of synucleinopathies characterized by alpha- synuclein (a-syn) aggregates in neurons referred to as Lewy bodies (LBs) and Lewy neurites (LNs) in PD/PDD/DLB or as glial cytoplasmic inclusions (GCIs) in oligodendrocytes of MSA. Recent findings suggest that progression of LBD could reflect the cell-to-cell spread of pathological a-syn strains in the nervous system followed by progressive neurodegeneration. Thus, this Udall Center renewal focuses on the progression of PD/PDD/DLB (Projects I/II) and mechanisms of CNS cell-to-cell spread of pathological a-syn (Projects III/ IV). Projects III and IV showed that MSA may result from a unique a-syn GCI strain that spreads among oligodendroglial cells and is distinct from those linked to LBs/LNs in neurons of LBD. Hence, these distinct strains of pathological a-syn will be analyzed in parallel in Projects III/IV. Core C supports the Udall Center goals by implementing postmortem diagnostic criteria for LBD and MSA while also assessing the utility of antemortem diagnostics including studies of potential genetic signatures. Core C works closely with all Cores/Projects to support the Center's mission by improving diagnostic methods, and providing samples of brain tissue and DNA to investigators within and beyond the Penn Udall Center.